US7741507B2 - Process for preparing Valsartan - Google Patents
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- US7741507B2 US7741507B2 US11/491,638 US49163806A US7741507B2 US 7741507 B2 US7741507 B2 US 7741507B2 US 49163806 A US49163806 A US 49163806A US 7741507 B2 US7741507 B2 US 7741507B2
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- PWTSUXSITXNQAN-XFULWGLBSA-N S.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C)C(C)C)C=C1 Chemical compound S.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C)C(C)C)C=C1 PWTSUXSITXNQAN-XFULWGLBSA-N 0.000 description 5
- 0 *C(C)N.*C(C)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)C(=O)CCCC.*C(C)N(CC1=CC=C(C2=CC=CC=C2[N+]#[C-])C=C1)C(=O)CCCC.*C(C)NCC1=CC=C(C2=CC=CC=C2[N+]#[C-])C=C1.CCCCC(=O)Cl.Cl.F.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CBr)C=C1 Chemical compound *C(C)N.*C(C)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)C(=O)CCCC.*C(C)N(CC1=CC=C(C2=CC=CC=C2[N+]#[C-])C=C1)C(=O)CCCC.*C(C)NCC1=CC=C(C2=CC=CC=C2[N+]#[C-])C=C1.CCCCC(=O)Cl.Cl.F.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CBr)C=C1 0.000 description 2
- JOZZAIIGWFLONA-RXMQYKEDSA-N CC(C)[C@@H](C)N Chemical compound CC(C)[C@@H](C)N JOZZAIIGWFLONA-RXMQYKEDSA-N 0.000 description 2
- PVCBGNQYDJVRNK-RZMTYUFWSA-N CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)[C@H](C(=O)O)C(C)C.S.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C)C(C)C)C=C1 Chemical compound CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)[C@H](C(=O)O)C(C)C.S.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C)C(C)C)C=C1 PVCBGNQYDJVRNK-RZMTYUFWSA-N 0.000 description 2
- VYBWVRVDHNFBTG-UHFFFAOYSA-N [C-]#[N+]C1=CC=CC=C1C1=CC=C(CC)C=C1 Chemical compound [C-]#[N+]C1=CC=CC=C1C1=CC=C(CC)C=C1 VYBWVRVDHNFBTG-UHFFFAOYSA-N 0.000 description 2
- UMZPCHCBBFZGHS-OAHLLOKOSA-N [C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C)C(C)C)C=C1 Chemical compound [C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C)C(C)C)C=C1 UMZPCHCBBFZGHS-OAHLLOKOSA-N 0.000 description 2
- NCQGKAPHUDNUHE-GHEIHMRFSA-N B.C.C.CCCCC(=O)Cl.CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)[C@H](C(=O)O)C(C)C.COC(=O)[C@@H](N)C(C)C.F.I.[2HH].[C-]#[N+]C1=CC=CC=C1C1=CC=C(C=O)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CBr)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN(C(=O)CCCC)[C@H](C(=O)OC)C(C)C)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C(=O)OC)C(C)C)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CO)C=C1 Chemical compound B.C.C.CCCCC(=O)Cl.CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)[C@H](C(=O)O)C(C)C.COC(=O)[C@@H](N)C(C)C.F.I.[2HH].[C-]#[N+]C1=CC=CC=C1C1=CC=C(C=O)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CBr)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN(C(=O)CCCC)[C@H](C(=O)OC)C(C)C)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C(=O)OC)C(C)C)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CO)C=C1 NCQGKAPHUDNUHE-GHEIHMRFSA-N 0.000 description 1
- TUHCCXMFPSGSHQ-IVUVMKSYSA-N C.CC(C)[C@@H](C)N.II.I[IH]I.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CC)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN(CC2=CC=C(C3=C(C#N)C=CC=C3)C=C2)[C@H](C)C(C)C)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C)C(C)C)C=C1 Chemical compound C.CC(C)[C@@H](C)N.II.I[IH]I.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CC)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN(CC2=CC=C(C3=C(C#N)C=CC=C3)C=C2)[C@H](C)C(C)C)C=C1.[C-]#[N+]C1=CC=CC=C1C1=CC=C(CN[C@H](C)C(C)C)C=C1 TUHCCXMFPSGSHQ-IVUVMKSYSA-N 0.000 description 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)[C@H](C(=O)O)C(C)C Chemical compound CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)[C@H](C(=O)O)C(C)C ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N CCCCC(C)=O Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- LGFCRPGOUZTNQW-LJQANCHMSA-N [C-]#[N+]C1=CC=CC=C1C1=CC=C(CN(C(=O)CCCC)[C@H](C)C(C)C)C=C1 Chemical compound [C-]#[N+]C1=CC=CC=C1C1=CC=C(CN(C(=O)CCCC)[C@H](C)C(C)C)C=C1 LGFCRPGOUZTNQW-LJQANCHMSA-N 0.000 description 1
- IXCIYEKLEXCEDA-RUZDIDTESA-N [C-]#[N+]C1=CC=CC=C1C1=CC=C(CN(CC2=CC=C(C3=C(C#N)C=CC=C3)C=C2)[C@H](C)C(C)C)C=C1 Chemical compound [C-]#[N+]C1=CC=CC=C1C1=CC=C(CN(CC2=CC=C(C3=C(C#N)C=CC=C3)C=C2)[C@H](C)C(C)C)C=C1 IXCIYEKLEXCEDA-RUZDIDTESA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/04—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines without replacement of the other oxygen atom of the carboxyl group, e.g. imino-ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
Definitions
- the present invention relates to novel compound of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester organic acid salt of formula (IV), which is useful as an intermediate for the preparation of Valsartan of formula (I), chemically known as (S)—N-(1-Carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine.
- Valsartan is useful as an antihypertensive.
- the present invention also relates to a process for preparing Valsartan using novel intermediate of formula (IV),
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl and S represents organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like.
- Valsartan belongs to group of angiotensin II antagonists which are useful in the treatment of hypertension, anxiety, glaucoma and cardiac attacks.
- Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. It is useful in regulating high blood pressure and cardiac insufficiency.
- the synthesis involves the conversion of 4-bromomethyl-2′-cyanobiphenyl of formula (A) to carbaldehyde of formula (C). Further, it is condensed with methyl ester of L-valine of formula (D) under reducing condition to give N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (E), which is purified by flash chromatography. Reaction of compound of formula (E) with n-Valeroyl chloride of formula (F) in presence of triethylamine gives N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (G). After purification by flash chromatography, compound of formula (G) is cyclized in presence of tributyltin azide in xylene and converted to Valsartan (I) in presence of sodium hydroxide.
- the carbaldehyde compound (C) is condensed with Tosylate salt of L-valine benzyl ester in presence of sodium cyanoborohydride to give benzyl ester analogue of compound of formula (E).
- This compound is purified by converting it into its hydrochloride salt and then breaking the hydrochloride salt with sodium bicarbonate. The purified compound is then reacted with n-Valeroyl chloride and cyclized with tributyltin azide in xylene. Further hydrogenation using Palladised carbon catalyst gives Valsartan (I).
- R is —CH(CH 3 ) 2 in above scheme represents Valsartan(I).
- the inventors of the present invention has surprisingly found that the dimeric impurity of formula (IVb) can be easily removed from desired compound of formula (IVa) by converting it into organic salt of formula (IV), which can be condensed directly with n-valeroyl chloride without further purification. Thus cumbersome technique of separation like column chromatography can be avoided.
- the compound of formula (IV) is stable and non-hygroscopic in nature. The use of compound (IV) in synthesis of Valsartan results in improved quality of product containing less percentage of impurities.
- the object of the present invention is to provide an improved process for the preparation of Valsartan of formula (I).
- Another object of the invention is to provide a novel compound of formula (IV) and its process for the preparation
- Yet another object of the present invention is to provide a process for preparing Valsartan by using novel intermediate, which is simple and easy to handle and cost effective.
- the principal aspect of the present invention relates to a novel compound of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester organic acid salt of formula (IV)
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl and S represents organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like.
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl; in presence of base and solvent, optionally in presence of catalyst; to form N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)valine ester derivative of formula (IVa).
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl.
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl;
- S represents organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like.
- Valsartan (I) comprising:
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl; in presence of base and solvent, optionally in presence of catalyst; to form N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester derivative of formula (IVa)
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl;
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, 2-methylpropyl or benzyl;
- S represents organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like
- R 1 represents C 1 -C 4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl
- novel compound of formula (IV) which is organic acid salt of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester.
- N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester of formula (IVa) is an useful intermediate for the synthesis of Valsartan (I). It can be prepared by reaction of 4-halomethyl-2′-cyanobiphenyl of formula (II) with L-valine ester derivative of formula (III). It is observed that this reaction gives compound of formula (IVa) containing about 6-10% by weight of unwanted dimeric impurity of formula (IVb). This impurity is difficult to remove by conventional methods of purification such as crystallization and column chromatography. Moreover, this results in the poor yield and quality of Valsartan and requires additional purification.
- the inventors of the present invention found the novel compound of formula (IV), which is an organic acid salt of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester, which does not yields the dimeric impurity and does not require additional purification.
- the novel compound of formula (IV) is substantially free form the dimeric impurity of formula (IVb).
- the reaction of 4-halomethyl-2′-cyanobiphenyl of formula (II) with L-valine ester derivative of formula (III) is carried out in presence of base in solvent.
- the base can be selected from the group comprising of organic base, inorganic base or mixtures thereof, more preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, ammonia, triethyl amine, pyridine and the like and most preferably sodium carbonate and potassium carbonate.
- Solvent can be selected form dimethylformamide, dimethylsulfoxide, acetonitrile, xylene or toluene, halogenated hydrocarbon such as methylenedichloride, ethylenedichloride or chloroform, alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-Amyl alcohol, isoamyl alcohol or tert-amyl alcohol or mixtures thereof.
- halogenated hydrocarbon such as methylenedichloride, ethylenedichloride or chloroform
- alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-Amyl alcohol, isoamyl alcohol or tert-amyl alcohol or mixtures thereof.
- the reaction is carried out optionally in presence of catalyst selected from alkaline earth metal halide like sodium iodide or potassium iodide. It acts as a promoter or an activator for condensation of halogen compound of formula (II) with L-valine ester derivative of formula (III).
- catalyst selected from alkaline earth metal halide like sodium iodide or potassium iodide. It acts as a promoter or an activator for condensation of halogen compound of formula (II) with L-valine ester derivative of formula (III).
- the reaction is carried out at temperature ranging from about 0° C. to about boiling temperature of the solvent, more preferably at about 30° C. to about 50° C.
- the reaction time varies from about 1 hour to about 10 hours, more preferably from about 2 hours to about 5 hours.
- the organic acid can be selected from group comprising of oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like.
- Solvent can be selected from water, methanol, ethanol, propanol, isopropanol, tert-butanol, toluene, n-hexane, o-xylene, n-heptane, methylenedichloride, ethylenedichloride, acetonitrile, dimethylformamide, dimethylsulfoxide or mixture thereof, more preferably water, o-xylene or mixtures thereof.
- the conversion takes place in about 5 hours, more preferably in about 1 hour.
- the organic acid salt of formula (IV) is then isolated and dried by conventional methods.
- 4-bromomethyl-2′-cyanobiphenyl, L-valine methyl ester, potassium carbonate and potassium iodide are taken in acetonitrile.
- the reaction mixture was stirred at about 40-45° C. for about 3 to 4 hours and the solvent was removed under vacuum.
- Water and xylene was added to reaction mass and the organic layer was separated.
- a solution of oxalic acid was added to the organic layer and stirred for about an hour at ambient temperature to give N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester oxalate salt.
- Base can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, ammonia, triethyl amine, pyridine and the like, more preferably sodium carbonate or potassium carbonate.
- Solvent can be selected from group comprising of methylene dichloride, chloroform, ethylene dichloride, xylene, toluene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, more preferably xylene.
- the reaction is carried out in temperature ranging form about 0° C. to the boiling point of the solvent, more preferably from about 0° C. to about 45° C. and most preferably at about 0° C. to about 5° C.
- the reaction takes place in about 1 hour to about 10 hours, more preferably about 2 hours to about 3 hours.
- the compound of formula (VI) is isolated by regular work-up procedures and can be used in the next step of cyclization without further purification.
- the reaction mixture is washed with aqueous basic solution to bring pH to neutral and the organic layer is separated.
- the organic layer can be used directly for the next step of cyclization without isolating compound of formula (IV).
- Valsartan of formula (I) Conversion of compound of formula (IV) to Valsartan of formula (I) can be carried out by conventional methods reported in prior art like use of tributyltin azide, tributyltin chloride and sodium azide, etc. in presence of solvent and subsequent de-protection. De-protection can be carried out in presence of base and solvent or by catalytic hydrogenation depending on the nature of L-valine ester derivative (III)
- N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester oxalate salt was taken in xylene followed by addition of aqueous potassium carbonate solution and valeroyl chloride at about 0-5° C. After completion of the reaction, the organic layer was washed with basic solution of sodium bicarbonate and separated. Tributyltin chloride and sodium azide was added to the organic layer and refluxed for about 20-25 hours. Further 10% sodium hydroxide solution was added to it and stirred for about 20-25 hours at ambient temperature to facilitate deprotection of methyl group. After regular work-up procedures, Valsartan was obtained.
- Valsartan can be purified by conventional methods. Alternatively it is possible to purify Valsartan by base-acid treatment.
- the crude Valsartan is dissolved in solvent preferably dichloromethane and solution of aqueous base preferably sodium bicarbonate is added to it till neutral pH. Further the layers are separated to remove impurities and the aqueous layer is charcoalized and filtered.
- organic solvent preferably dichloromethane is added to it and the pH is adjusted to about 3-4 using acetic acid. The organic layer is separated and concentrated to obtain residue. Cyclohexane is added to this residue to form slurry which is stirred at ambient temperature for about an hour followed by filtration to obtain pure Valsartan.
- reaction mixture is cooled to ambient temperature and a 1000 ml of 10% sodium hydroxide solution is added to the reaction mixture and stirred at ambient temperature of 20-25 hours.
- layers are separated and 1000 ml dichloromethane is added to the aqueous layer, 200 ml of acetic acid is added to it till pH 3-4 is obtained and stirred for about 30 minutes.
- the layers are separated and the organic layer is washed with brine solution.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl and S represents organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like.
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl and S represents organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like.
wherein X represents halogen selected from Cl or Br, with L-Valine ester derivative of formula (III)
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl; in presence of base and solvent, optionally in presence of catalyst; to form N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)valine ester derivative of formula (IVa).
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl.
(b) treating N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester derivative of formula (IVa) with organic acid to obtain compound of formula (IV).
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl; S represents organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like.
- (a) reacting 4-halomethyl-2′-cyanobiphenyl of formula (II)
wherein X represents halogen selected from Cl or Br, with L-valine ester derivative of formula (III)
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl; in presence of base and solvent, optionally in presence of catalyst; to form N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester derivative of formula (IVa)
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl;
- (b) treating N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine ester derivative of formula (IVa) with organic acid to obtain compound of formula (IV).
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, 2-methylpropyl or benzyl; S represents organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like
- (c) acylating the compound of formula (IV) with Valeroyl halide of formula (V)
wherein X is halogen selected from Cl or Br; in the presence of base and water, optionally in organic solvent; to obtain compound of formula (VI)
wherein R1 represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or benzyl
- (d) Converting the compound of formula (VI) to obtain compound formula (I) by the method such as here in described or by the conventional method.
Claims (4)
Priority Applications (1)
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US12/815,950 US7923567B2 (en) | 2005-08-22 | 2010-06-15 | Process for preparing valsartan |
Applications Claiming Priority (2)
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US12/815,950 Division US7923567B2 (en) | 2005-08-22 | 2010-06-15 | Process for preparing valsartan |
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US12/815,950 Expired - Fee Related US7923567B2 (en) | 2005-08-22 | 2010-06-15 | Process for preparing valsartan |
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EP (1) | EP1926705B3 (en) |
JP (1) | JP2009504800A (en) |
KR (1) | KR20080039510A (en) |
AT (1) | ATE441627T1 (en) |
BR (1) | BRPI0614836A2 (en) |
CA (1) | CA2619955A1 (en) |
DE (1) | DE602006008962D1 (en) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110237822A1 (en) * | 2008-04-07 | 2011-09-29 | Hetero Research Foundation | Process for preparation of valsartan intermediate |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
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US7880015B2 (en) * | 2006-07-03 | 2011-02-01 | Aurobindo Pharma Ltd. | Process for the preparation of angiotensin II antagonist |
EP2152678A1 (en) | 2007-05-07 | 2010-02-17 | Cipla Limited | Process for preparing valsartan |
JP2010526126A (en) * | 2007-05-07 | 2010-07-29 | シプラ・リミテッド | Method for producing valsartan |
US7943794B2 (en) * | 2008-02-13 | 2011-05-17 | Ranbaxy Laboratories Limited | Processes for the preparation of intermediates of valsartan |
KR101009404B1 (en) * | 2008-04-30 | 2011-01-19 | 켐젠주식회사 | Preparation of high purity S-N-1-carboxy-2-methyl-pro-1-phyl-N-pentanoyl-N-[2?-1H-tetrazol-5-ylbiphenyl-4-yl-methyl]amine |
KR101012135B1 (en) * | 2008-12-18 | 2011-02-07 | 주식회사 대희화학 | Process for preparing Valsartan methyl ester |
EP2316821A1 (en) * | 2009-10-27 | 2011-05-04 | Novartis AG | Process for the manufacture of organic compounds |
WO2012001484A2 (en) * | 2010-07-02 | 2012-01-05 | Aurobindo Pharma Limited | An improved process for the preparation of valsartan |
CN102417486B (en) * | 2012-01-04 | 2013-11-27 | 合肥工业大学 | Method for synthesizing valsartan |
CN105001173A (en) * | 2015-06-30 | 2015-10-28 | 浙江天顺生物科技有限公司 | Preparation method of LZ969 |
CN112778159A (en) * | 2021-02-19 | 2021-05-11 | 安徽云帆药业有限公司 | Synthesis method of valsartan intermediate |
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US5399578A (en) * | 1990-02-19 | 1995-03-21 | Ciba-Geigy Corp | Acyl compounds |
US20030068374A1 (en) * | 2000-02-21 | 2003-04-10 | Shigeru Kamei | Sustained release preparations of physiologically active compound hardly soluble in water and production process and use of the same |
US6589547B1 (en) * | 1998-03-04 | 2003-07-08 | Takeda Chemical Industries, Ltd. | Sustained-release preparation for AII antagonist, production and use thereof |
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JPH11322697A (en) * | 1998-05-12 | 1999-11-24 | Sumika Fine Chemicals Co Ltd | Production of, n-((2'-cyanobiphenyl-4-yl)methyl)-l-valine benzyl ester and new salt of the same compound |
WO2005049588A1 (en) * | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for isolation of valsartan |
WO2005049587A1 (en) * | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for preparation of biphenyl tetrazole |
US7659406B2 (en) * | 2005-01-03 | 2010-02-09 | Dr. Reddy's Laboratories Limited | Process for preparing valsartan |
US20060281801A1 (en) * | 2005-04-19 | 2006-12-14 | Ashok Kumar | Process for the preparation of valsartan and its intermediates |
-
2006
- 2006-06-29 WO PCT/IN2006/000220 patent/WO2007032019A2/en active Application Filing
- 2006-06-29 CA CA002619955A patent/CA2619955A1/en not_active Abandoned
- 2006-06-29 ES ES06832282T patent/ES2333169T3/en active Active
- 2006-06-29 KR KR1020087007098A patent/KR20080039510A/en not_active Application Discontinuation
- 2006-06-29 JP JP2008527597A patent/JP2009504800A/en active Pending
- 2006-06-29 AT AT06832282T patent/ATE441627T1/en not_active IP Right Cessation
- 2006-06-29 EP EP06832282A patent/EP1926705B3/en not_active Not-in-force
- 2006-06-29 BR BRPI0614836-0A patent/BRPI0614836A2/en not_active IP Right Cessation
- 2006-06-29 DE DE602006008962T patent/DE602006008962D1/en active Active
- 2006-07-24 US US11/491,638 patent/US7741507B2/en not_active Expired - Fee Related
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2010
- 2010-06-15 US US12/815,950 patent/US7923567B2/en not_active Expired - Fee Related
Patent Citations (3)
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US5399578A (en) * | 1990-02-19 | 1995-03-21 | Ciba-Geigy Corp | Acyl compounds |
US6589547B1 (en) * | 1998-03-04 | 2003-07-08 | Takeda Chemical Industries, Ltd. | Sustained-release preparation for AII antagonist, production and use thereof |
US20030068374A1 (en) * | 2000-02-21 | 2003-04-10 | Shigeru Kamei | Sustained release preparations of physiologically active compound hardly soluble in water and production process and use of the same |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110237822A1 (en) * | 2008-04-07 | 2011-09-29 | Hetero Research Foundation | Process for preparation of valsartan intermediate |
US8492577B2 (en) * | 2008-04-07 | 2013-07-23 | Hetero Research Foundation | Process for preparation of valsartan intermediate |
Also Published As
Publication number | Publication date |
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JP2009504800A (en) | 2009-02-05 |
EP1926705A2 (en) | 2008-06-04 |
US7923567B2 (en) | 2011-04-12 |
KR20080039510A (en) | 2008-05-07 |
WO2007032019A2 (en) | 2007-03-22 |
BRPI0614836A2 (en) | 2012-12-04 |
DE602006008962D1 (en) | 2010-07-08 |
EP1926705B1 (en) | 2009-09-02 |
US20060258878A1 (en) | 2006-11-16 |
WO2007032019A3 (en) | 2007-06-14 |
WO2007032019B1 (en) | 2007-07-26 |
EP1926705B3 (en) | 2010-09-15 |
US20100249430A1 (en) | 2010-09-30 |
ATE441627T1 (en) | 2009-09-15 |
CA2619955A1 (en) | 2007-03-22 |
ES2333169T3 (en) | 2010-02-17 |
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